Pyrazolopyrimidines as cyclin dependent kinase inhibitors

ABSTRACT

In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

This application is a Divisional of U.S. application Ser. No.11/395,824, filed Mar. 31, 2006, which is a Divisional of U.S.application Ser. No. 10/653,868, filed Sep. 3, 2003, and claims thebenefit of U.S. Provisional Application Ser. No. 60/407,999, filed Sep.4, 2002.

FIELD OF THE INVENTION

The present invention relates to pyrazolo[1,5-a]pyrimidine compoundsuseful as protein kinase inhibitors, pharmaceutical compositionscontaining the compounds, and methods of treatment using the compoundsand compositions to treat diseases such as, for example, cancer,inflammation, arthritis, viral diseases, neurodegenerative diseases suchas Alzheimer's disease, cardiovascular diseases, and fungal diseases.

BACKGROUND OF THE INVENTION

The cyclin-dependent kinases (CDKs) are serine/threonine proteinkinases, which are the driving force behind the cell cycle and cellproliferation. Individual CDK's, such as, CDK1, CDK2, CDK3, CDK4, CDK5,CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycleprogression and can be classified as either G1, S, or G2M phase enzymes.Uncontrolled proliferation is a hallmark of cancer cells, andmisregulation of CDK function occurs with high frequency in manyimportant solid tumors. CDK2 and CDK4 are of particular interest becausetheir activities are frequently misregulated in a wide variety of humancancers. CDK2 activity is required for progression through G1 to the Sphase of the cell cycle, and CDK2 is one of the key components of the G1checkpoint. Checkpoints serve to maintain the proper sequence of cellcycle events and allow the cell to respond to insults or toproliferative signals, while the loss of proper checkpoint control incancer cells contributes to tumorgenesis. The CDK2 pathway influencestumorgenesis at the level of tumor suppressor function (e.g. p52, RB,and p27) and oncogene activation (cyclin E). Many reports havedemonstrated that both the coactivator, cyclin E, and the inhibitor,p27, of CDK2 are either over—or underexposed, respectively, in breast,colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin'slymphoma, ovarian, and other cancers. Their altered expression has beenshown to correlate with increased CDK2 activity levels and poor overallsurvival. This observation makes CDK2 and its regulatory pathwayscompelling targets for the development years, a number of adenosine5′-triphosphate (ATP) competitive small organic molecules as well aspeptides have been reported in the literature as CDK inhibitors for thepotential treatment of cancers. U.S. Pat. No. 6,413,974, col. 1, line23-col. 15, line 10 offers a good description of the various CDKs andtheir relationship to various types of cancer.

CDK inhibitors are known. For example, flavopiridol (Formula I) is anonselective CDK inhibitor that is currently undergoing human clinicaltrials, A. M. Sanderowicz et al., J. Clin. Oncol. (1998) 16, 2986-2999.

Other known inhibitors of the CDKs include, for example, olomoucine (J.Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I.Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. Pat. No.6,107,305 describes certain pyrazolo[3,4-b]pyridine compounds as CDKinhibitors. An illustrative compound from the '305 patent has theFormula II:

K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162disclose certain aminothiazole compounds as CDK inhibitors.

Pyrazolopyrimidines are known. For Example, WO92/18504, WO02/50079,WO95/35298, WO02/40485, EP94304104.6, EP0628559 (equivalent to U.S. Pat.Nos. 5,602,136, 5,602,137 and 5,571,813), U.S. Pat. No. 6,383,790, Chem.Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med.Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 disclosevarious pyrazolopyrimidines.

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with CDKs. It is,therefore, an object of this invention to provide compounds useful inthe treatment or prevention or amelioration of such diseases anddisorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofpyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependentkinases, methods of preparing such compounds, pharmaceuticalcompositions comprising one or more such compounds, methods of preparingpharmaceutical formulations comprising one or more such compounds, andmethods of treatment, prevention, inhibition or amelioration of one ormore diseases associated with the CDKs using such compounds orpharmaceutical compositions.

In one aspect, the present application discloses a compound, orpharmaceutically acceptable salts or solvates of said compound, saidcompound having the general structure shown in Formula III:

wherein:

Q is —S(O₂)— or —C(O)—;

R is aryl or heteroaryl, wherein said aryl or heteroaryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, CN, —OR⁵,SR⁵, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —NR⁵R⁶, —C(O)NR⁵R⁶, CF₃, alkyl, aryl andOCF₃;

R² is selected from the group consisting of CN, NR⁵R⁶, —C(O₂)R⁶,—C(O)NR⁵R⁶, —OR⁶, —SR⁶, —S(O₂)R⁷, —S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; alkynyl, heteroaryl, CF₃,heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R⁹groups which can be the same or different and are independently selectedfrom the list of R⁹ shown below,

R³ is selected from the group consisting of H, halogen, —NR⁵R⁶,—C(O)NR⁵R⁶, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl,

wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl for R³ and theheterocyclyl moieties whose structures are shown immediately above forR³ can be substituted or optionally independently substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, CN, —OCF₃, —(CR⁴R⁵)_(n)OR⁵, —OR⁵, —NR⁵R⁶,—(CR⁴R⁵)_(n)NR⁵R⁶, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R⁶, —SR⁶, —S(O₂)R⁶,—S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶;

R⁴ is H, halo or alkyl;

R⁵ is H or alkyl;

R⁶ is selected from the group consisting of H, alkyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl can be unsubstituted or optionally substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, heterocyclylalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R¹⁰,—N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H,—SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R¹⁰ is selected from the group consisting of H, alkyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl can be unsubstituted or optionally substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, heterocyclylalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁴R⁵,—N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)NR⁴R⁵, —C(O)R⁵, —SO₃H, —SR⁵,—S(O₂)R⁷, —S(O₂)NR⁴R⁵, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁴R⁵;

-   -   or optionally (i) R⁵ and R¹⁰ in the moiety —NR⁵R¹⁰, or (ii) R⁵        and R⁶ in the moiety —NR⁵R⁶, may be joined together to form a        cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl        or heterocyclyl moiety being unsubstituted or optionally        independently being substituted with one or more R⁹ groups;

R⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl,cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵,—C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰, —S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰,—N(R⁵)C(O)R¹⁰ and —N(R⁵)C(O)NR⁵R¹⁰;

R⁸ is selected from the group consisting of R⁶, —C(O)NR⁵R¹⁰,—S(O₂)NR⁵R¹⁰, —C(O)R⁷ and —S(O₂)R⁷;

R⁹ is selected from the group consisting of halogen, CN, —NR⁵R¹⁰,—C(O₂)R⁶, —C(O)NR⁵R¹⁰, —OR⁶, —SR⁶, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰,—N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰;

m is 0 to 4, and

n is 1 to 4.

The compounds of Formula III can be useful as protein kinase inhibitorsand can be useful in the treatment and prevention of proliferativediseases, for example, cancer, inflammation and arthritis. They may alsobe useful in the treatment of neurodegenerative diseases suchAlzheimer's disease, cardiovascular diseases, viral diseases and fungaldiseases.

DETAILED DESCRIPTION

In one embodiment, the present invention disclosespyrazolo[1,5-a]pyrimidine compounds which are represented by structuralFormula III, or a pharmaceutically acceptable salt or solvate thereof,wherein the various moieties are as described above.

In another embodiment, R is selected from the group consisting ofphenyl, naphthyl, 2-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridyl-N-oxide,3-pyridyl-N-oxide, 1,3-thiazol-2-yl, pyrimidin-5-yl, pyrazin-3-yl andpyridazin-3-yl.

In another embodiment, R² is CF₃, CN, cycloalkyl, —OR⁶, —C(O)OR⁴,—CH₂OR⁶, aryl or heteroaryl.

In another embodiment, R³ is H, alkyl, unsubstituted aryl, unsubstitutedheteroaryl, aryl substituted with one or more moieties selected from thegroup consisting of halogen, CN, —OR⁵, CF₃, —OCF₃, lower alkyl andcycloalkyl, heterocyclyl, heteroaryl substituted with one or moremoieties selected from the group consisting of halogen, CN, —OR⁵, CF₃,—OCF₃, alkyl and cycloalkyl,

In another embodiment, R⁴ is H or lower alkyl.

In another embodiment, R⁵ is H or lower alkyl.

In another embodiment, m is 0 to 2.

In another embodiment, n is 1 or 2.

In an additional embodiment, R is selected from the group consisting ofphenyl, 2-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridyl-N-oxide,3-pyridyl-N-oxide, 1,3-thiazol-2-yl and pyrimidin-5-yl.

In an additional embodiment, R² is CF₃, CN or cycloalkyl.

In an additional embodiment, R³ is H, lower alkyl, cycloalkyl, C(O)OR⁴or aryl wherein said alkyl and aryl are unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from thegroup consisting of F, Cl, Br, CF₃, lower alkyl, methoxy, and CN, or

In an additional embodiment, R⁴ is H.

In an additional embodiment, R⁵ is H.

In an additional embodiment, m is 0.

In an additional embodiment, R is 2-pyridyl, 3-pyridyl, 4-pyridyl,N-oxide of 4-pyridyl, or the N-oxide of 3-pyridyl.

In an additional embodiment, R² is cyclopropyl, cyclobutyl orcyclopentyl.

In an additional embodiment, R³ is methyl, ethyl, isopropyl, tert-butyl,heteroaryl, Cl, unsubstituted phenyl, phenyl substituted with one ormore moieties selected from the group consisting of F, Br, Cl, OMe, CH₃and CF₃,

In an additional embodiment, R³ is:

In an additional embodiment, R⁸ is (CH₂)_(n)OH or (CH₂)_(n)OCH₃, where nis 1 or 2.

In an additional embodiment, R³ is furanyl

An inventive group of compounds are shown in Table 1.

TABLE 1

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl and t-butyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— andY₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, and aralkyl.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protected moieties are also consideredpart of this invention. The heterocyclyl can be optionally substitutedby one or more “ring system substituents” which may be the same ordifferent, and are as defined herein. The nitrogen or sulfur atom of theheterocyclyl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclicheterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula III, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula III or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the CDK(s) and thus producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula III can form salts which are also within thescope of this invention. Reference to a compound of Formula III hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula III contains both a basic moiety, such as, but not limited toa pyridine or imidazole, and an acidic moiety, such as, but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful Salts of the compoundsof the Formula III may be formed, for example, by reacting a compound ofFormula III with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of Formula III, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the sails,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention, as are positional isomers (such as, forexample, 4-pyridyl and 3-pyridyl). Individual stereoisomers of thecompounds of the invention may, for example, be substantially free ofother isomers, or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention can have the S or R configuration as defined by theIUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”“prodrug” and the like, is intended to equally apply to the salt,solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers,positional isomers, racemates or prodrugs of the inventive compounds.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula III can beinhibitors of protein kinases such as the cyclin dependent kinases(CDKs), for example, CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7 and CDK8.The novel compounds of Formula III are expected to be useful in thetherapy of proliferative diseases such as cancer, autoimmune diseases,viral diseases, fungal diseases, neurological/neurodegenerativedisorders, arthritis, inflammation, anti-proliferative (e.g., ocularretinopathy), neuronal, alopecia and cardiovascular disease. Many ofthese diseases and disorders are listed in U.S. Pat. No. 6,413,974 citedearlier, the disclosure of which is incorporated herein.

More specifically, the compounds of Formula III can be useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing:

carcinoma, including that of the bladder, breast, colon, kidney, liver,lung, including small cell lung cancer, esophagus, gall bladder, ovary,pancreas, stomach, cervix, thyroid, prostate, and skin, includingsquamous cell carcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Due to the key role of CDKs in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

Compounds of Formula III may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that CDK5 isinvolved in the phosphorylation of tau protein (J. Biochem, (1995) 117,741-749).

Compounds of Formula III may induce or inhibit apoptosis. The apoptoticresponse is aberrant in a variety of human diseases. Compounds ofFormula III, as modulators of apoptosis, will be useful in the treatmentof cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited toherpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), prevention of AIDS development in HIV-infected individuals,autoimmune diseases (including but not limited to systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus), neurodegenerative disorders (including but notlimited to Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis,cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

Compounds of Formula III, as inhibitors of the CDKs, can modulate thelevel of cellular RNA and DNA synthesis. These agents would therefore beuseful in the treatment of viral infections (including but not limitedto HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barrvirus, Sindbis virus and adenovirus).

Compounds of Formula III may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of Formula III may also be useful in inhibiting tumorangiogenesis and metastasis.

Compounds of Formula III may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abland thus be effective in the treatment of diseases associated with otherprotein kinases.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition associated with the CDKs byadministering a therapeutically effective amount of at least onecompound of Formula III, or a pharmaceutically acceptable salt orsolvate of said compound to the mammal.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula III. An especially preferred dosage is about 0.01 to25 mg/kg of body weight/day of a compound of Formula III, or apharmaceutically acceptable salt or solvate of said compound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more of anti-cancertreatments such as radiation therapy, and/or one or more anti-canceragents selected from the group consisting of cytostatic agents,cytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil); anti-metabolites (such asmethotrexate); alkylating agents (such as temozolomide (TEMODAR™ fromSchering-Plough Corporation, Kenilworth, N.J.), cyclophosphamide);Farnesyl protein transferase inhibitors (such as,SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide,or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.),tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor from Merck & Company,Whitehouse Station, N.J.), BMS 214662 (a farnesyl protein transferaseinhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.);signal transduction inhibitors (such as, Iressa (from Astra ZenecaPharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodiesto EGFR (e.g., C225), GLEEVEC™ (C-abl kinase inhibitor from NovartisPharmaceuticals, East Hanover, N.J.); interferons such as, for example,intron (from Schering-Plough Corporation), Peg-intron (fromSchering-Plough Corporation); hormonal therapy combinations; aromatasecombinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovorin,oxaliplatin (ELOXATIN™ from Sanofi-Synthelabo Pharmaceuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, orHexamethylmelamine.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. For example, the CDC2 inhibitor olomucine has been found to actsynergistically with known cytotoxic agents in inducing apoptosis (J.Cell Sci., (1995) 108, 2897. Compounds of Formula III may also beadministered sequentially with known anticancer or cytotoxic agents whena combination formulation is inappropriate The invention is not limitedin the sequence of administration; compounds of Formula III may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of Formula III, or apharmaceutically acceptable salt or solvate thereof, and an amount ofone or more anti-cancer treatments and anti-cancer agents listed abovewherein the amounts of the compounds/treatments result in desiredtherapeutic effect.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described later have been carried outwith the compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula III, or a pharmaceuticallyacceptable salt or solvate of said compound and at least onepharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula III, or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula III, or a pharmaceutically acceptable saltor solvate of said compound and an amount of at least one anticancertherapy and/or anti-cancer agent listed above, wherein the amounts ofthe two or more ingredients result in desired therapeutic effect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz) or XL-400 (400MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min-10% CH₃CN, 5 min-95% CH₃CN, 7 min-95% CH₃CN, 7.5min-10% CH₃CN, 9 min-stop. The retention time and observed parent ionare given.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   Thin layer chromatography: TLC-   dichloromethane: CH₂Cl₂-   ethyl acetate: AcOEt or EtOAc-   methanol: MeOH-   trifluoroacetate: TFA-   triethylamine: Et₃N or TEA-   butoxycarbonyl: n-Boc or Boc-   nuclear magnetic resonance spectroscopy: NMR-   liquid chromatography mass spectrometry: LCMS-   high resolution mass spectrometry: HRMS-   milliliters: mL-   millimoles: mmol-   microliters: μl-   grams: g-   milligrams: mg-   room temperature or rt (ambient): about 25° C.-   N-bromosuccinimide: NBS-   N-chlorosuccinimide: NCS

EXAMPLES

In general, the compounds described in this invention can be preparedthrough the general routes described below, Treatment of the startingnitrile (Scheme 1) with potassium t-butoxide and ethyl formate givesrise to the intermediate enol 2 which upon treatment with hydrazinegives the desired substituted 3-aminopyrazole. Condensation of compoundsof type 3 with the appropriately functionalized keto ester of type 5gives rise to the pyridones 6 as shown on in Scheme 3. The keto estersused in this general route are either commercially available or can bemade as illustrated in Scheme 2.

The chlorides of type 7 can be prepared by treatment of the pyridones 6with POCl₃. When R² is equal to H, substitution in this position ispossible on compounds of type 9 by electrophilic halogenation,acylation, and various other electrophilic aromatic substitutions.

Incorporation of the N7-amino functionality can be accomplished throughdisplacement of the chloride of compounds of type 9 with ammonia.(Scheme 3). Acylation with an appropriately substituted acid chloride orsulfonyl chloride gives the desired compounds of type 10.

When R³=OEt in compounds of type 6, the dichlorides of type 12 caneasily be prepared as outlined in Scheme 4. Selective displacements ofthe 7-chloride gives rise to compounds of type 13, which can readily beconverted to products of type 14 or the corresponding sulfonamides.

Preparative Example 1

Step A:

A procedure in German patent DE 19834047 A1, p 19 was followed. To asolution of KOtBu (6.17 g, 0.055 mol) in anhydrous THF (40 mL) wasadded, dropwise, a solution of cyclopropylacetonitrile (2.0 g, 0.025mol) and ethyl formate (4.07 g, 0.055 mol) in anhydrous THF (4 mL). Aprecipitate formed immediately. This mixture was stirred for 12 hr. Itwas concentrated under vacuum and the residue stirred with Et₂O (50 mL).The resulting residue was decanted and washed with Et₂O (2×50 mL) andEt₂O removed from the residue under vacuum. The residue was dissolved incold H₂O (20 mL) and the pH adjusted to 4-5 with 12N HCl. The mixturewas extracted with CH₂Cl₂ (2×50 mL). The organic layers were combined,dried over MgSO₄ and concentrated under vacuum to give the aldehyde as atan liquid.

Step B:

The product from Preparative Example 1, Step A (2.12 g, 0.0195 mol),NH₂NH₂. H₂O (1.95 g, 0.039 mol) and 1.8 g (0.029 mole) of glacialCH₃CO₂H (1.8 g, 0.029 mol) were dissolved in EtOH (10 mL). The mixturewas refluxed for 6 hr and concentrated under vacuum. The residue wasslurried in CH₂Cl₂ (150 mL) and the pH adjusted to with 1 N NaOH. Theorganic layer was washed with brine, dried over MgSO₄ and concentratedunder vacuum to give the product as a waxy orange solid.

Preparative Examples 2-3

By essentially the same procedure set forth in Preparative Example 1,only substituting the nitrile shown in Column 2 of Table 2, thecompounds in Column 3 of Table 2 were prepared:

TABLE 2 Prep. Ex. Column 2 Column 3 2

3

Preparative Example 4

The reactions were done as outlined in (Olsen, K. O. J. Org. Chem.,(1987) 52, 4531-4536). Thus, to a stirred solution of lithiumdiisopropylamide in THF at −65 to −70° C. was added freshly distilledethyl acetate, dropwise. The resulting solution was stirred for 30 minand the acid chloride was added as a solution in THF. The reactionmixture was stirred at −65 to −70° C. for 30 min and then terminated bythe addition of 1 N HCl solution. The resulting two-phased mixture wasallowed to warm to ambient temperature. The resulting mixture wasdiluted with EtOAc (100 mL) the organic layer was collected. The aqueouslayer was extracted with EtOAc (100 mL). The organic layers werecombined, washed with brine, dried (Na₂SO₄), and concentrated in vacuoto give the crude β-keto esters, which were used in the subsequentcondensations.

Preparative Examples 5-10

By following essentially the same procedure set forth in PreparativeExample 4 only substituting the acid chlorides shown in Column 2 ofTable 3, the β-keto esters shown in Column 3 of Table 3 were prepared:

TABLE 3 Prep. Ex. Column 2 Column 3 DATA 5

Yield = 99%LCMS: MH⁺ = 223 6

Yield = 99%LCMS: MH⁺ = 253 7

Yield = 80%LCMS: MH⁺ = 261 8

Yield = 93%LCMS: MH⁺ = 199 9

Yield = 93% 10

Yield = 100%

Preparative Example 11

To a solution of the acid in THF was added Et₃N, followed by isobutylchloroformate at −20 to −30° C. After the mixture was stirred for 30 minat −20 to −30° C., triethylamine hydrochloride was filtered off underargon, and the filtrate was added to the LDA-EtOAc reaction mixture(prepared as outlined in Method A) at −65 to −70 C, After addition of 1N HCl, followed by routine workup of the reaction mixture andevaporation of the solvents, the crude β-keto esters were isolated. Thecrude material was used in the subsequent condensations.

Preparative Examples 12-14

By following essentially the same conditions set forth in PreparativeExample 11 only substituting the carboxylic acid shown in Column 2 ofTable 4, the compounds shown in Column 3 of Table 4 were prepared:

TABLE 4 Prep. Ex. Column 2 Column 3 DATA 12

Yield = 99MH⁺ 199 13

Yield = 99MH⁺ 334 14

Yield = 99MH⁺ 334

Preparative Example 15

A solution of 3-aminopyrazole (2.0 g, 24.07 mmol) and ethylbenzoylacetate (4.58 mL, 1.1 eq.) in AcOH (15 mL) was heated at refluxfor 3 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The resulting solid was diluted with EtOAc andfiltered to give a white solid (2.04 g, 40% yield).

Preparative Examples 16-37

By essentially the same procedure set forth in Preparative Example 15only substituting the aminopyrazole shown in Column 2 of Table 5 and theester shown in Column 3 of Table 5, the compounds shown in Column 4 ofTable 5 were prepared:

TABLE 5 Prep. Ex. Column 2 Column 3 Column 4 16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

Preparative Example 38

Ethyl benzoylacetate (1.76 mL, 1.1 eq.) and 3-amino-4-cyanopyrazole (1.0g, 9.25 mmol) in AcOH (5.0 mL) and H₂O (10 mL) was heated at reflux 72hours. The resulting solution was cooled to room temperature,concentrated in vacuo, and diluted with EtOAc. The resulting precipitatewas filtered, washed with EtOAc, and dried in vacuo (0.47 g, 21% yield).

Preparative Example 39

A procedure in U.S. Pat. No. 3,907,799 was followed. Sodium (2.3 g, 2eq.) was added to EtOH (150 mL) portionwise. When the sodium wascompletely dissolved, 3-aminopyrazole (4.2 g, 0.05 mol) and diethylmalonate (8.7 g, 1.1 eq.) were added and the resulting solution heatedto reflux for 3 hours. The resulting suspension was cooled to roomtemperature and filtered. The filter cake was dissolved in H₂O, the pHadjusted to 1-2 with concentrated HCl and the resulting solid wasfiltered, washed with H₂O (100 mL) and dried under vacuum to give awhite solid (4.75 g, 63% yield).

Preparative Examples 40-41

By essentially the same procedure set forth in Preparative Example 39only substituting the compound shown in Column 2 of Table 6, thecompounds shown in Column 3 of Table 6 are prepared:

TABLE 6 Prep. Ex. Column 2 Column 3 40

41

Preparative Example 42

A solution of the compound prepared in Preparative Example 15 (1.0 g,4.73 mmol) in POCl₃ (5 mL) and pyridine (0.25 mL) was stirred at roomtemperature 3 days. The resulting slurry was diluted with Et₂O,filtered, and the solid residue washed with Et₂O. The combined Et₂Owashings were cooled to 0° C. and treated with ice. When the vigorousreaction ceased, the resulting mixture was diluted with H₂O, separatedthe aqueous layer extracted with Et₂O. The combined organics were washedwith H₂O and saturated NaCl, dried over Na₂SO₄, filtered, andconcentrated to give a pale yellow solid (0.86 g, 79% yield). LCMS:MH⁺=230.

Preparative Example 43-65

By following essentially the same procedure set forth in PreparativeExample 42, only substituting the compound shown in Column 2 of Table 7,the compounds shown in Column 3 of Table 7 were prepared:

TABLE 7 Prep. Ex. Column 2 Column 3 DATA 43

LCMS:MH⁺ = 248 44

— 45

LCMS:MH⁺ = 298 46

LCMS:MH⁺ = 196 47

LCMS:MH⁺ = 210 48

— 49

— 50

— 51

LCMS:MH⁺ = 255 52

— 53

Yield = 65%LCMS: MH⁺ =260 54

Yield = 35%LCMS: MH⁺ =290 55

Yield = 32%LCMS: MH⁺ =298 56

Yield = 45%LCMS: MH⁺ =236 57

Yield = 30%LCMS: MH⁺ =295 58

Yield = 98%LCMS: MH⁺ =244 59

60

61

Yield = 96MH⁺ = 371 62

63

Yield = 99MH⁺ = 371 64

65

Yield =quant.MH⁺ = 236

Preparative Example 66

To a solution of the compound from Preparative Example 42 (1.0 g, 4.35mmol) in DMF (6 mL) was added POCl₃ (1.24 mL, 3.05 eq.) and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was cooled to 0° C. and the excess POCl₃ was quenchedby the addition of ice. The resulting solution was neutralized with 1NNaOH, diluted with H₂O, and extracted with CH₂Cl₂. The combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography using a 5% MeOH in CH₂Cl₂solution as eluent (0.95 g, 85% yield), LCMS: MH⁺=258.

Preparative Example 67

To a solution of PPh₃ (4.07 g, 4.0 eq.) and CBr₄ (2.57 g, 2.0 eq.) inCH₂Cl₂ (75 mL) at 0° C. was added the compound prepared in PreparativeExample 168 (1.0 g, 3.88 mmol). The resulting solution was stirred at 0°C. for 1 hour and concentrated under reduced pressure. The residue waspurified by flash chromatography using a 20% EtOAc in hexanes solutionas eluent (1.07 g, 67% yield).

Preparative Example 68

POCl₃ (62 mL) was cooled to 5° C. under nitrogen and dimethylaniline(11.4 g, 2.8 eq.) and the compound prepared in Preparative Example 39(4.75 g, 0.032 mol). The reaction mixture was warmed to 60° C. andstirred overnight. The reaction mixture was cooled to 30° C. and thePOCl₃ was distilled off under reduced pressure. The residue wasdissolved in CH₂Cl₂ (300 mL) and poured onto ice. After stirring 15minutes, the pH of the mixture was adjusted to 7-8 with solid NaHCO₃.The layers were separated and the organic layer was washed with H₂O(3×200 mL), dried over MgSO₄, filtered, and concentrated. The crudeproduct was purified by flash chromatography using a 50:50 CH₂Cl₂:hexanes solution as eluent to elute the dimethyl aniline. The eluent wasthen changed to 75:25 CH₂Cl₂: hexanes to elute the desired product (4.58g, 77% yield). MS: MH⁺=188.

Preparative Examples 69-70

By essentially the same procedure set forth in Preparative Example 68only substituting the compound in Column 2 of Table 8, the compoundsshown in Column 3 of Table 8 are prepared:

TABLE 8 Prep. Ex. Column 2 Column 3 69

70

Preparative Example 71

A solution of the compound prepared in Preparative Example 42 (0.10 g,0.435 mmol) in CH₃CN (3 mL) was treated with NBS (0.085 g, 1.1 eq.). Thereaction mixture was stirred at room temperature 1 hour and concentratedunder reduced pressure. The crude product was purified by flashchromatography using an 20% EtOAc in hexanes solution as eluent (0.13 g,100% yield). LCMS: MH⁺=308.

Preparative Examples 72-90

By essentially the same procedure set forth in Preparative Example 71using NBS or NIS and substituting the compounds shown in Column 2 ofTable 9, the compounds shown in Column 3 of Table 9 are prepared:

TABLE 9 Prep. Ex. Column 2 Column 3 DATA 72

LCMS:MH⁺ = 357 73

LCMS:MH⁺ = 326 74

LCMS:MH⁺ = 342 75

LCMS:MH⁺ = 274 76

LCMS:MH⁺ = 288 77

LCMS:MH⁺ = 342 78

Yield = 75%LCMS: MH⁺ =338 79

Yield = 52%LCMS: MH⁺ =368 80

Yield = 87%LCMS: MH⁺ =376 81

Yield = 100%LCMS: MH⁺ =316 82

Yield = 100%LCMS: MH⁺ =322 83

84

85

86

Yield = 99MH⁺ = 449 87

Yield = 95MH⁺ = 449 88

MH⁺ = 266 89

90

Yield = quant.MH⁺ = 314

Preparative Example 91

The compound prepared in Preparative Example 71 (3.08 g) 10.0 mmol), 2.0M NH₃ in 2-propanol (50 mL, 100.0 mmol), and 37% aqueous NH₃ (10.0 mL)were stirred in a closed pressure vessel at 50° C. for 1 day. Thesolvent was evaporated and the crude product was purified by flashchromatography using 3:1 CH₂Cl₂:EtOAc as eluent. Pale yellow solid (2.30g 80%) was obtained. LCMS: M⁺289.

Preparative Examples 92-101

By essentially the same procedure set forth in Preparative Example 91only substituting the compounds shown in Column 2 of Table 10 thecompounds shown in column 3 of Table 10 are prepared

TABLE 10 Prep. Ex. Column 2 Column 3 92

93

94

95

96

97

98

99

100

101

Preparative Example 102

A mixture of the compound prepared in Preparative Example 95 (0.50mmol), and DMAP (0.66 mmol) in anhydrous dioxane (10 mL) is stirred at25° C. under N₂, then Boc₂O (1.20 mmol) is added and the mixture isstirred at 25° C. for 20 hr. The reaction mixture is poured intosaturated aqueous NaHCO₃ (100 mL) and extracted with CH₂Cl₂ (3×30 mL).Combined extracts are dried over Na₂SO₄, filtered, and the solvent isevaporated. The residue is purified by flash chromatography to give thedesired product.

Preparative Examples 103-106

By essentially the same procedure set forth in Preparative Example 102only substituting the compounds shown in Column 2 of Table 11, thecompound shown in Column 3 of Table 11 are prepared.

TABLE 11 Prep. Ex. Column 2 Column 3 103

104

105

106

Preparative Example 107

A mixture of the compound prepared in Preparative Example 102 (1.00mmol), triethyl(trifluoromethyl)silane (3.60 mmol), potassium fluoride(3.60 mmol), and CuI (4.46 mmol) in anhydrous DMF (4 mL) is stirred in aclosed pressure vessel at 80° C. for 72 hr. CH₂Cl₂ (80 mL) is added andthe mixture is filtered through Celite. The solvent is evaporated andthe residue is purified by flash chromatography to give the desiredproduct.

Preparative Examples 108-109

By essentially the same procedure set forth in Preparative Example 107only substituting the compounds shown in Column 2 of Table 12 thecompound shown in Column 3 of Table 12 are prepared.

TABLE 12 Prep. Ex. Column 2 Column 3 108

109

Preparative Example 110

To a solution of the compound prepared in Preparative Example 106 (0.21mmol) in THF (4.0 mL) at −78° C. is added nBuLi (2.16M in hexanes, 5.0eq.) at −78° C. The reaction mixture is stirred 2 hours at −78° C.,quenched with H₂O, warmed to room temperature, and extracted with EtOAc.The combined organics are dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product is purified by Preparative TLCto yield the desired product.

Preparative Example 111

TFA is added at 0° C. under N₂ to a stirred solution of the compoundprepared in Preparative Example 107 in anhydrous CH₂Cl₂. The mixture isstirred at 0° C. for 10 min, then at 25° C. for 2 hr. It is poured into10% aqueous Na₂CO₃ (50 mL), extracted with CH₂Cl₂ (3×15 mL), dried overNa₂SO₄, and filtered. The solvent is evaporated and the residue ispurified by flash chromatography to give the desired product.

Preparative Examples 112-114

By essentially the same procedure set forth in Example only substitutingthe compounds shown in Column 2 of Table 13, the compound shown inColumn 3 of Table 13 are prepared.

TABLE 13 Prep. Ex. Column 2 Column 3 112

113

114

Example 1

The product from Preparative Example 92 (1.0 eq.), isonicotinoylchloride hydrochloride (1.1 eq.), and pyridine (2.5 eq.) are stirred inCH₂Cl₂ for 24 hours. The reaction mixture is diluted with saturatedNaHCO₃ and extracted with CH₂Cl₂. The combined organics are dried overNa₂SO₄, filtered, and concentrated. The crude product is purified byflash chromatography.

Examples 2-11

By following essentially the same procedure set forth in Example 1, onlysubstituting the compounds in Column 2 of Table 14, the compounds inColumn 3 of Table 14 are prepared.

TABLE 14 Ex. Column 2 Column 3 2

3

4

5

6

7

8

9

10

11

Example 12

The product from Preparative Example 107 (1.0 eq.), 4-pyridylsulfonylchloride hydrochloride (1.1 eq.), and pyridine (2.5 eq.) are stirred inCH₂Cl₂ for 24 hours. The reaction mixture is diluted with saturatedNaHCO₃ and extracted with CH₂Cl₂. The combined organics are dried overNa₂SO₄, filtered, and concentrated. The crude product is purified byflash chromatography.

Examples 13-22

By following essentially the same procedure set forth in Example 12 onlysubstituting the compounds in Column 2 of Table 15, the compounds inColumn 3 of Table 15 are prepared:

TABLE 15 Ex. Column 2 Column 3 13

14

15

16

17

18

19

20

21

22

Example 23

Step A:

To a solution the compound prepared in Example 6 in dioxane/DIPEA(2.5/1.0) at rt is added cyclopentylamine (1.2 eq.) dropwise. Theresulting solution is stirred at reflux for 16 h, cooled to rt, andconcentrated under reduced pressure. The crude material is purified bypreparative thin-layer chromatography (8×1000 μM).

Step B:

To a solution of the compound prepared in Example 23, Step A in CH₂Cl₂at rt is added TFA (5 eq.) dropwise. The resulting solution is stirredfor 18 h at rt and is concentrated under reduced pressure. The crudematerial is redissolved in CH₂Cl₂ and the organic layer is sequentiallywashed with sat. aq. NaHCO₃ (2×2 mL) and brine (1×2 mL). The organiclayer is dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The crude material is purified by preparative thin-layerchromatography (8×1000 μM).

Examples 24-33

By essentially the same procedure set forth in Example 23 onlysubstituting the chlorides in Column 2 of Table 16 the compounds shownin Column 3 of Table 16 are prepared.

TABLE 16 Ex. Column 2 Column 3 24

25

26

27

28

29

30

31

32

33

Example 34

To a solution of the compound prepared in Example 10 in anhydrousacetonitrile is added TMSI (4 eq.), dropwise at ambient temperature.After 10 minutes the acetonitrile is removed in vacuo. The resultingyellow foam is treated with 2 N HCl solution (7 mL) and then washedimmediately with Et₂O (5×). The pH of the aqueous is adjusted to 10 with50% NaOH (aq) and the product is isolated by saturation of the solutionwith NaCl (s) followed by extraction with CH₂Cl₂ (5×) to give thedesired product.

Examples 35-37

By essentially the same procedure set forth in Example 34 onlysubstituting the compounds shown in Column 2 of Table 17, the compoundsshown in Column 3 of Table 17 were prepared.

TABLE 17 Ex. Column 2 Column 3 35

36

37

ASSAY: The assay on the compounds of the present invention may beperformed as follows.

BACULOVIRUS CONSTRUCTIONS: Cyclin E is cloned into pVL1393 (Pharmingen,La Jolla, Calif.) by PCR, with the addition of 5 histidine residues atthe amino-terminal end to allow purification on nickel resin. Theexpressed protein is approximately 45 kDa. CDK2 is cloned into pVL1393by PCR, with the addition of a hemaglutinin epitope tag at thecarboxy-terminal end (YDVPDYAS). The expressed protein is approximately34 kDa in size.

ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclin E andCDK2 are co-infected into SF9 cells at an equal multiplicity ofinfection (MOI=5), for 48 hrs. Cells are harvested by centrifugation at1000 RPM for 10 minutes, then pellets lysed on ice for 30 minutes infive times the pellet volume of lysis buffer containing 50 mM Tris pH8.0, 150 mM NaCl, 1% NP40, 1 mM DTT and protease inhibitors (RocheDiagnostics GmbH, Mannheim, Germany). Lysates are spun down at 15000 RPMfor 10 minutes and the supernatant retained. 5 ml of nickel beads (forone liter of SF9 cells) are washed three times in lysis buffer (QiagenGmbH, Germany). Imidazole is added to the baculovirus supernatant to afinal concentration of 20 mM, then incubated with the nickel beads for45 minutes at 4° C. Proteins are eluted with lysis buffer containing 250mM imidazole. Eluate is dialyzed overnight in 2 liters of kinase buffercontaining 50 mM Tris pH 8.0, 1 mM DTT, 10 mM MgCl2, 100 uM sodiumorthovanadate and 20% glycerol. Enzyme is stored in aliquots at −70° C.

IN VITRO KINASE ASSAY: Cyclin E/CDK2 kinase assays are performed in lowprotein binding 96-well plates (Corning Inc, Corning, N.Y.). Enzyme isdiluted to a final concentration of 50 μg/ml in kinase buffer containing50 mM Tris pH 8.0, 10 mM MgCl₂, 1 mM DTT, and 0.1 mM sodiumorthovanadate. The substrate used in these reactions is a biotinylatedpeptide derived from Histone H1 (from Amersham, UK). The substrate isthawed on ice and diluted to 2 μM in kinase buffer. Compounds arediluted in 10% DMSO to desirable concentrations. For each kinasereaction, 20 μl of the 50 μg/ml enzyme solution (1 μg of enzyme) and 20μl of the 2 μM substrate solution are mixed, then combined with 10 μl ofdiluted compound in each well for testing. The kinase reaction isstarted by addition of 50 μl of 2 μM ATP and 0.1 μCi of 33P-ATP (fromAmersham, UK). The reaction is allowed to run for 1 hour at roomtemperature. The reaction is stopped by adding 200 μl of stop buffercontaining 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg/mlstreptavidin coated SPA beads (from Amersham, UK) for 15 minutes. TheSPA beads are then captured onto a 96-well GF/B filter plate(Packard/Perkin Elmer Life Sciences) using a Filtermate universalharvester (Packard/Perkin Elmer Life Sciences.). Non-specific signalsare eliminated by washing the beads twice with 2M NaCl then twice with 2M NaCl with 1% phosphoric acid. The radioactive signal is then measuredusing a TopCount 96 well liquid scintillation counter (fromPackard/Perkin Elmer Life Sciences).

IC₅₀ DETERMINATION. Dose-response curves are be plotted from inhibitiondata generated, each in duplicate, from 8 point serial dilutions ofinhibitory compounds. Concentration of compound is plotted against %kinase activity, calculated by CPM of treated samples divided by CPM ofuntreated samples. To generate IC₅₀ values, the dose-response curves arethen fitted to a standard sigmoidal curve and IC₅₀ values are derived bynonlinear regression analysis.

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

1. A method of treating breast cancer by inhibiting a cyclin dependentkinase in a patient, comprising administering a therapeuticallyeffective amount of at least one compound represented by the structuralformula III:

wherein: Q is —S(O₂)— or —C(O)—; R is aryl or heteroaryl, wherein saidaryl or heteroaryl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, CN, —OR⁵, SR⁵, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —NR⁵R⁶,—C(O)NR⁵R⁶, CF₃, alkyl, aryl and OCF₃; R² is selected from the groupconsisting of CN, NR⁵R⁶, —C(O₂)R⁶, —C(O)NR⁵R⁶, —OR⁶, —SR⁶, —S(O₂)R⁷,—S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; alkynyl,heteroaryl, CF₃, heterocyclyl, alkynylalkyl, cycloalkyl, alkylsubstituted with 1-6 R⁹ groups which can be the same or different andare independently selected from the list of R⁹ shown below,

R³ is selected from the group consisting of H, halogen, —NR⁵R⁶,—C(O)NR⁵R⁶ alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl,

wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl for R³ and theheterocyclyl moieties whose structures are shown immediately above forR³ can be substituted or optionally independently substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, CN, —OCF₃, —(CR⁴R⁵)_(n)OR⁵, —OR⁵, —NR⁵R⁶,—(CR⁴R⁵)_(n)NR⁵R⁶, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R⁶, —SR⁶, —S(O₂)R⁶,—S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; R⁴ is H,halo or alkyl; R⁵ is H or alkyl; R⁶ is selected from the groupconsisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of saidalkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)R⁵,—C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; R¹⁰ is selected from the groupconsisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of saidalkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁴R⁵, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵,—C(O)NR⁴R⁵, —C(O)R⁵, —SO₃H, —SR⁵, —S(O₂)R⁷, —S(O₂)NR⁴R⁵, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁴R⁵; or optionally (i) R⁵ and R¹⁰ in themoiety —NR⁵R¹⁰, or (ii) R⁵ and R⁶ in the moiety —NR⁵R⁶, may be joinedtogether to form a cycloalkyl or heterocyclyl moiety, with each of saidcycloalkyl or heterocyclyl moiety being unsubstituted or optionallyindependently being substituted with one or more R⁹ groups; R⁷ isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl,cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵,—C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰, —S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰,—N(R⁵)C(O)R¹⁰ and —R⁵)C(O)NR⁵R¹⁰; R⁸ is selected from the groupconsisting of R⁶, —C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷ and —S(O₂)R⁷; R⁹ isselected from the group consisting of halogen, CN, —NR⁵R¹⁰, —C(O₂)R⁶,—C(O)NR⁵R¹⁰, —OR⁶, —SR⁶, S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; m is 0 to 4, or a pharmaceuticallyacceptable salt thereof to said patient, wherein said cyclin dependentkinase is CDK1 or CDK2.
 2. The method of claim 1, wherein said kinase isCDK2.
 3. The method of claim 1 wherein said compound is administeredalong with an amount of at least one second compound, said secondcompound being selected from the group consisting of cytostatic agent,cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies toEGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracilmustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,leucovirin, ELOXATIN™, Pentostatine, Vinbiastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethyistilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,or Hexamethylmelamine, anti-cancer agent; wherein the amounts of thefirst compound and said second compound result in a therapeutic effect.4. The method of claim 3, further comprising radiation therapy.
 5. Themethod of claim 3, wherein said first compound is administered to saidpatient, together, concurrently or sequentially, with said secondcompound, wherein said second compound is temozolomide.
 6. A method oftreating breast cancer, comprising administering a therapeuticallyeffective amount of at least one compound selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 7. A method of treatingbreast a cancer, comprising administering to a mammal in need of suchtreatment an amount of a first compound, which is a compound describedin claim 6, and an amount of at least one second compound selected fromthe group consisting of, cytostatic agent, cisplatin, doxorubicin,taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan,paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777,L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec,intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard,Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethyistilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,or Hexamethylmelamine; wherein the amounts of the first compound andsaid second compound result in a therapeutic effect.
 8. The method ofclaim 7, further comprising radiation therapy.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound represented by the structural formula III:

wherein: Q is —S(O₂)— or —C(O)—; R is aryl or heteroaryl, wherein saidaryl or heteroaryl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, CN, —OR⁵, SR⁵, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —NR⁵R⁶,—C(O)NR⁵R⁶, CF₃, alkyl, aryl and OCF₃; R² is selected from the groupconsisting of CN, NR⁵R⁶, —C(O₂)R⁶, —C(O)NR⁵R⁶, —OR⁶, —SR⁶, —S(O₂)R⁷,—S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; alkynyl,heteroaryl, CF₃, heterocyclyl, alkynylalkyl, cycloalkyl, alkylsubstituted with 1-6 R⁹ groups which can be the same or different andare independently selected from the list of R⁹ shown below,

R³ is selected from the group consisting of H, halogen, —NR⁵R⁶,—C(O)NR⁵R⁶, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl,

wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl for R³ and theheterocyclyl moieties whose structures are shown immediately above forR³ can be substituted or optionally independently substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, CN, —OCF₃, —(CR⁴R⁵)_(n)OR⁵, —OR⁵, —NR⁵R⁶,—(CR⁴R⁵)_(n)NR⁵R⁶, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R⁶, —SR⁶, —S(O₂)R⁶,—S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; R⁴ is H,halo or alkyl; R⁵ is H or alkyl; R⁶ is selected from the groupconsisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of saidalkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)R⁵,—C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; R¹⁰ is selected from the groupconsisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of saidalkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁴R⁵, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵,—C(O)NR⁴R⁵, —C(O)R⁵, —SO₃H, —SR⁵, —S(O₂)R⁷, —S(O₂)NR⁴R⁵, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁴R⁵; or optionally (i) R⁵ and R¹⁰ in themoiety —NR⁵R¹⁰, or (ii) R⁵ and R⁶ in the moiety —NR⁵R⁶, may be joinedtogether to form a cycloalkyl or heterocyclyl moiety, with each of saidcycloalkyl or heterocyclyl moiety being unsubstituted or optionallyindependently being substituted with one or more R⁹ groups; R⁷ isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl,cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵,—C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰, —S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰,—N(R⁵)C(O)NR¹⁰ and —N(R⁵)C(O)NR⁵R¹⁰; R⁸ is selected from the groupconsisting of R⁶, —C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷ and —S(O₂)R⁷; R⁹ isselected from the group consisting of halogen, CN, —NR⁵R¹⁰, —C(O₂)R⁶,—C(O)NR⁵R¹⁰, —OR⁶, —SR⁶, —S(O₂)NR⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; m is 0 to 4, and n is 1 to 4 incombination with at least one pharmaceutically acceptable carrieradditionally comprising temozolomide.
 10. A method of breast treatingcancer in a patient, comprising administering a therapeuticallyeffective amount of a pharmaceutical composition comprising the compounddescribed in claim 6 in combination with at least one pharmaceuticallyacceptable carrier to said patient.